Widespread errors in 'proofreading' cause inherited blindness

This new understanding of the disease process, published today in Nature Communications, is leading to the development of a gene therapy for RP caused by splicing factor defects.

The work, led by Professor Majlinda Lako at Newcastle University, investigated how a common form of inherited blindness, retinitis pigmentosa, is caused by genetic defects in splicing factors.

Factors - Components - Gene - Proofreading - Mechanism

Splicing factors are important protein components of the gene proofreading or "splicing" mechanism that is found in all cells. Some sections of our DNA, known as introns, are removed or spliced out by the cell during protein construction, so that only the final intelligible genetic code remains. This is because the introns do not actually provide any meaningful instructions for making proteins. Variations in splicing can cause very different consequences on the formation or function of cells, including retinal cells.

The scientists were able to create a "retina in a dish" using stem cells derived from the skin samples donated by retinitis pigmentosa patients at the University of Leeds.

Cell - Model - Team - Cells - Others

This cell model enabled the team to compare retinal cells to others in the body. These cells are normally very hard to obtain as they would previously have had to be donated from the retina, usually after death.

Using this model, the researchers have shown that defects in splicing factors cause defective proofreading of components of the editing machinery itself. This counter-intuitive effect results in a "vicious cycle" of disruptive misinterpretation of the genetic code. The formation and functions of a special type of retinal cells, retinal pigment epithelial (RPE) cells, are the most severely affected. These cells are essential for supporting and nourishing photoreceptors (rod and cone cells), so when they go wrong the light-processing function of the retina breaks down, resulting in sight loss.

Study - Shows - Time - Defects - Factors

The study shows, for the first time, how genetic defects in splicing factors cause variations...